Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide with an annual incidence of over 550,000, predominantly affecting patients with cirrhosis and chronic hepatitis. Current American Association for the Study of Liver Diseases (AASLD) practice guidelines recommend ultrasound (US) for HCC surveillance, and CT and MRI for diagnosis of HCC in patients with nodules detected by surveillance US. Contrast-enhanced ultrasound (CEUS) has been extensively studied for liver imaging. Multiple pilot and single-institution studies have demonstrated high specificity and positive predictive value of CEUS for HCC diagnosis, comparable to hepatobiliary agent gadoxetate-enhanced MRI. Based on that, World Federation of Ultrasound in Medicine and Biology and European Federation of Societies for Ultrasound in Medicine and Biology in their joint guidelines recommended use of arterial phase hyperenhancement with contrast washout on CEUS to diagnose HCC. However it has not been tested in a multicenter setting in patients at risk for HCC. A recent development that has the potential to improve clinical acceptance of CEUS is the introduction of the CEUS Liver Imaging Reporting and Data System (CEUS LI-RADS) introduced by the American College of Radiology. This system provides standardization of CEUS examination, imaging findings and reporting, and allows liver nodule classification based on their likelihood to be HCC. However, this system has not been clinically validated. We hypothesize that the high diagnostic value of CEUS for HCC diagnosis will be confirmed in a multicenter setting, providing a safe and accurate imaging technique for focal liver nodule characterization, including in patients with contraindications to CT and/or MRI, such as such as allergic reactions to contrast, claustrophobia, metallic implants or foreign bodies or renal insufficiency. In addition, we hypothesize that use of CEUS LI-RADS will decrease user-dependency of CEUS. A total of 640 patients will be included in this international multicenter study. All patients will receive CEUS and results will be compared to a rigorous composite imaging and tissue histology reference standard to determine the diagnostic value of CEUS for HCC diagnosis clinical validity of CEUS LIRADS classification. This project will also establish user-dependency of CEUS and address factors that might potentially limit its clinical use.